Alzheimer;s disease is a progressive neurodegenerative disorder whose cause is unknown and for which no effective therapy exists. We propose a Drug Discovery Group with the major goal of conducting hypothesis- driven research into the process of discovery of efficacious drugs which affect underlying neurochemical alterations of Alzheimer's disease. The Program of Drug Discovery emanates from the current activities of two University of Florida Centers of excellence and the Mayo Clinic Jacksonville. Four separate gut related projects are proposed and their activities would be supported by 4 cores. Two projects would design, synthesize and evaluate compounds for their ability to improve intracellular calcium metabolism in models for the calcium disregulation associated with neurodegeneration in Alzheimer's disease. In Project 1, inositol bioisosteres would be synthesized which effect regulatory steps in the phosphoinositide and inositol polyphosphate modulation of intracellular calcium. Project 2 would evaluate the mechanisms, including calcium modulation, of the cytoprotective effects of selective nicotinic agonists. Projects 3 and 4 would address the important therapeutic issue of brain-targeted delivery of drugs with potential efficacy in Alzheimer's disease. Project 3 would apply molecular packaging technology to achieve the brain-targeted delivery of neuropeptides, with a particular focus on thyrotropin-releasing hormone. The chemistry developed in this project would be applicable to other neuroactive peptides. In Project 4, we would synthesize and evaluate brain-targeted chemical delivery systems for neurotrophomodulators for their efficacy in stimulating endogenous nerve growth factor secretion and the resulting cholinergic cytoprotection. Our strategy of drug discovery is to design and synthesize large numbers of candidate drugs early in each project and to use in project tests to determine their potential efficacy. Redesign, synthesis and retesting of compounds would narrow the number of drug candidates to be subjected to further evaluation. It is expected that 3 to 6 compounds will emerge from each project for further, intensive evaluations using animal models for the cholinergic hypofunction of Alzheimer's disease. Those drugs which show efficacy in tests of cytoprotection and/or memory enhancement would then be synthesized in quantities sufficient to conduct animal toxicity studies. In summary, this Program of Drug Discovery should result in novel compounds with potential efficacy in the treatment of the cognitive decline associated with Alzheimer's disease.